Background: Prolonged hypoglycemia leads to brain injury, despite treatment with 10% dextrose. Whether induction of hyperglycemia or ketonemia achieves better neuroprotection is unknown. Hyperglycemia is neuroprotective in other brain injuries during development; however, it worsens hypoglycemia-induced injury in the adult brain via poly(ADPribose)polymerase-1 (PARP-1) overactivation. Methods: Three-week-old rats were subjected to insulininduced hypoglycemia and treated with 10% dextrose or 50% dextrose. Neuronal injury, PARP-1, and brain-derived neurotrophic factor (BDNF) III/TrkB/p75 NTR expressions were determined. In the second experiment, ketonemia was induced by administering β-hydroxybutyrate during hypoglycemia and its effect on neuronal injury was compared with those conventionally treated using 10% dextrose. results: Both 10 and 50% dextrose administration led to hyperglycemia (50% dextrose > 10% dextrose). Compared with the 10% dextrose group, neuronal injury was greater in the 50% dextrose group and was accompanied by PARP-1 overactivation. BDNF III and p75 NTR , but not TrkB FL , mRNA expressions were upregulated. Neuronal injury was less severe in the rats subjected to ketonemia, compared with those conventionally treated using 10% dextrose. conclusion: Hyperglycemia accentuated hypoglycemiainduced neuronal injury, likely via PARP-1 overactivation. Although BDNF was upregulated, it was not neuroprotective and potentially exaggerated injury by binding to p75 NTR receptor. Conversely, ketonemia during hypoglycemia attenuated neuronal injury.